The purpose of this study is to assess whether expression of not only POLQ/Polθ, but also Shieldin complex and/or 53BP1 are correlated with primary and/or acquired resistance to PARPi (Poly(ADP-Ribose) Polymerases inhibitors) in a sub-population of locally advanced or metastatic breast cancer patients and vary regarding type and location of gBRCA1/2 mutations.

This translational research program is composed of two multicentric, non-randomized prospective studies in patients with HER2-negative locally advanced or metastatic breast cancer:

• The main study concerns 80 patients eligible for PARPi (according to the investigators).PARPi treatments (talazoparib or olaparib) will be administered and dosed according to the standard of care administration.
• The sub-study concerns 40 patients in progression disease under PARPi alone.

For each included patient in the main study or sub-study, tumor biopsy specimen and blood samples will be collected at different times during the study.

MAIN STUDY

INCLUSION CRITERIA:

1. Women (or men) aged ≥ 18 years with histologically proven breast cancer
2. Metastatic relapse or locally advanced breast cancer
3. No-HER2 overexpression or amplification
4. Triple-negative (defines as ER<1%, PR<1% and HER2-negative as per ASCO CAP guidelines) or hormone receptor positive (defines as ER and/or PR ≥ 1%) breast cancer
5. Patients with metastases that can be biopsied except bone metastases. At baseline, if patients already have an archived biopsy from a secondary or a primary site (if stage IV) of their current disease, this material can be used for the study, provided that, it was collected within 3 months prior enrollment and a frozen and a FFPE sample are both available for research
6. ECOG Performance Status ≤ 2
7. Patients must have measurable or evaluable disease according to RECIST v1.1
8. Patient with deleterious germline BRCA 1 and/or 2 mutation, eligible for PARP inhibitor therapy (olaparib or talazoparib), according each investigator
9. Any number of prior lines therapy are allowed
10. Current treatment with PARP inhibitor not yet started
11. Women should be post-menopaused or willing to accept the use of an effective contraceptive regimen during the treatment period by PARP inhibitor
12. Patient able to participate and willing to give informed consent prior performance of any study-related procedures and to comply with the study protocol
13. Patient affiliated to a Social Health Insurance in France

NON-INCLUSION CRITERIA:

1. Abnormal coagulation contraindicating biopsy
2. Bone metastases when this is the only site of biopsiable disease
3. Patients with all target in a previously irradiated region, except if clear progression has been observed prior to study in at least one of them
4. Patients with known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
5. Patients with known untreated CNS metastases and/or carcinomatous meningitis
6. Patients with a known history of Human Immunodeficiency Virus (HIV)
7. Patients with known active Hepatitis B or C
8. Patients should not be on any other anti-cancer therapy (chemotherapy, endocrine therapy, immunotherapy, tailored therapy or alternative investigational therapy)
9. Patient pregnant, or breast-feeding
10. Any psychological, familial, geographic or social situation, according to the judgment of investigator, potentially preventing the provision of informed consent or compliance to study procedure
11. Patient who has forfeited his/her freedom by administrative or legal award or who is under legal protection (curatorship and guardianship, protection of justice)

SUB-STUDY

INCLUSION CRITERIA:

1. Women (or men) aged ≥ 18 years with histologically proven breast cancer
2. Metastatic relapse or locally advanced breast cancer
3. No-HER2 overexpression or amplification
4. Triple-negative (defines as ER<1%, PR<1% and HER2-negative as per ASCO CAP guidelines) or hormone receptor positive (defines as ER and or PR ≥ 1%) breast cancer
5. Patients with metastases that can be biopsied except bone metastases
6. ECOG Performance Status ≤ 2
7. Patients, with deleterious germline BRCA 1 and/or 2, in progression under PARPi alone (talazoparib or olaparib)
8. Patient able to participate and willing to give informed consent prior performance of any study-related procedures and to comply with the study protocol
9. Patient affiliated to a Social Health Insurance in France

NON-INCLUSION CRITERIA:

1. Abnormal coagulation contraindicating biopsy
2. Bone metastases when this is the only site of biopsiable disease
3. Patient pregnant, or breast-feeding
4. Patients with a known history of Human Immunodeficiency Virus (HIV)
5. Patients with known active Hepatitis B or C
6. Any psychological, familial, geographic or social situation, according to the judgment of investigator, potentially preventing the provision of informed consent or compliance to study procedure
7. Patients already participating in the main REPARP study
8. Patient who has forfeited his/her freedom by administrative or legal award or who is under legal protection (curatorship and guardianship, protection of justice)